tbuckley/cabot-search huggingface dataset:
Genetically Modified Porcine-to-Human Cardiac Xenotransplantation
Authors: Bartley P. Griffith, Corbin E. Goerlich, Avneesh K. Singh, Martine Rothblatt, Christine L. Lau, Aakash Shah, Marc Lorber, Alison Grazioli, Kapil K. Saharia, Susie N. Hong, Susan M. Joseph, David Ayares, Muhammad M. Mohiuddin
Journal: New England Journal of Medicine (2022)

A 57-year-old man with nonischemic cardiomyopathy who was dependent on venoarterial extracorporeal membrane oxygenation (ECMO) and was not a candidate for standard therapeutics, including a traditional allograft, received a heart from a genetically modified pig source animal that had 10 individual gene edits. Immunosuppression was based on CD40 blockade. The patient was weaned from ECMO, and the xenograft functioned normally without apparent rejection. Sudden diastolic thickening and failure of the xenograft occurred on day 49 after transplantation, and life support was withdrawn on day 60. On autopsy, the xenograft was found to be edematous, having nearly doubled in weight. Histologic examination revealed scattered myocyte necrosis, interstitial edema, and red-cell extravasation, without evidence of microvascular thrombosis - findings that were not consistent with typical rejection. Studies are under way to identify the mechanisms responsible for these changes. (Funded by the University of Maryland Medical Center and School of Medicine.).
Matrix Metalloproteinases: From Molecular Mechanisms to Physiology, Pathophysiology, and Pharmacology
Authors: Luiz G.N. de Almeida, Hayley Thode, Yekta Eslambolchi, Sameeksha Chopra, Daniel Young, Sean Gill, Laurent Devel, Antoine Dufour
Journal: Pharmacological Reviews (2022)

The first matrix metalloproteinase (MMP) was discovered in 1962 from the tail of a tadpole by its ability to degrade collagen. As their name suggests, matrix metalloproteinases are proteases capable of remodeling the extracellular matrix. More recently, MMPs have been demonstrated to play numerous additional biologic roles in cell signaling, immune regulation, and transcriptional control, all of which are unrelated to the degradation of the extracellular matrix. In this review, we will present milestones and major discoveries of MMP research, including various clinical trials for the use of MMP inhibitors. We will discuss the reasons behind the failures of most MMP inhibitors for the treatment of cancer and inflammatory diseases. There are still misconceptions about the pathophysiological roles of MMPs and the best strategies to inhibit their detrimental functions. This review aims to discuss MMPs in preclinical models and human pathologies. We will discuss new biochemical tools to track their proteolytic activity in vivo and ex vivo, in addition to future pharmacological alternatives to inhibit their detrimental functions in diseases. <h3>Significance Statement</h3> Matrix metalloproteinases (MMPs) have been implicated in most inflammatory, autoimmune, cancers, and pathogen-mediated diseases. Initially overlooked, MMP contributions can be both beneficial and detrimental in disease progression and resolution. Thousands of MMP substrates have been suggested, and a few hundred have been validated. After more than 60 years of MMP research, there remain intriguing enigmas to solve regarding their biological functions in diseases.
NUDT1 promotes the accumulation and longevity of CD103+ TRM cells in primary biliary cholangitis
Authors: Bingyuan Huang, Zhuwan Lyu, Qiwei Qian, Yong Chen, Jun Zhang, Bo Li, Yikang Li, Jubo Liang, Qiaoyan Liu, You Li, Ruiling Chen, Min Lian, Xiao Xiao, Qi Miao, Qixia Wang, Jingyuan Fang, Zhexiong Lian, Yanmei Li, Ruqi Tang, Thomas Helleday, M. Eric Gershwin, Zhengrui You, Xiong Ma
Journal: Journal of Hepatology (2022)
Cancer cells depend on environmental lipids for proliferation when electron acceptors are limited
Authors: Zhaoqi Li, Brian W. Ji, Purushottam D. Dixit, Konstantine Tchourine, Evan C. Lien, Aaron M. Hosios, Keene L. Abbott, Justine C. Rutter, Anna M. Westermark, Elizabeth F. Gorodetsky, Lucas B. Sullivan, Matthew G. Vander Heiden, Dennis Vitkup
Journal: Nature Metabolism (2022)
P1295: DECIPHERING THE ROLE OF MSI2 AS A REGULATOR OF MANTLE CELL LYMPHOMA STEM-LIKE PROPERTIES
Authors: M. Sureda-Gómez, P. Balsas, M.-L. Rodríguez, F. Nadeu, A. De Bolòs, Á. Eguileor, M. Kulis, G. Castellano, E. Giné, S. Demajo, J. I. Martín-Subero, P. Jares, E. Campo, V. Amador
Journal: HemaSphere (2022)

Background: Mantle cell lymphoma (MCL) is a mature B cell neoplasm with two distinct biological subtypes regarding clinical, molecular and pathological features. Conventional MCL (cMCL) subtype is characterized by high aggressiveness and poor outcome with frequent relapses after initial response to treatment, suggesting the presence of a population of cells able to self-renew and responsible for drug resistance. SOX11 transcription factor, expressed in embryonic stem cells (ESC), is aberrantly overexpressed mostly in cMCL and has an oncogenic role in MCL. MCL-cancer stem cells have been isolated from MCL cases by different groups. However, its relationship to SOX11 expression and contribution to MCL pathogenesis and clinical evolution remain unknown. Aims: We hypothesized that SOX11 may promote stem cell-like properties through the activation of stem cell-related genes, leading to an aggressive and incurable tumor in MCL patients. We aimed to identify potential mediators of stemness directly regulated by SOX11 in MCL. Methods: Here, we integrated the differential gene expression profile between SOX11+ and SOX11- MCL primary cases with stem cell-related genes, specific SOX11 ChIP-chip bound genes and epigenomic data of MCLs. Results: SOX11+ MCL showed enrichment in leukemic (LSC) and hematopoietic stem cells (HSC) gene signatures compared to SOX11- MCL primary cases. Musashi-2 (MSI2), an RNA binding protein that maintains self-renewal and prevents differentiation in HSC and ESC, emerged as one of the most significant upregulated stem cell-related genes in SOX11+ MCLs. SOX11 directly bound to MSI2 regulatory regions increasing its expression in vitro in MCL cells. MSI2 enhancers located in intronic regions were strongly activated in SOX11+ but not in SOX11- MCL cell lines and primary cases. MSI2 upregulation significantly associated with chemoresistance and poor overall survival, independently of common risk factors (SOX11 expression, high copy number alterations, 17p/TP53, 11q/ATM and 9p/CDKN2A alterations), in MCL patients. MSI2 knockdown MCL cell lines had a gene expression profile enriched in proapoptotic-related genes; whereas HSC and LSC gene signatures were downregulated compared to its control cells. MSI2 knockdown or MSI2 inhibition with Ro 08-2750 treatment decreased clonogenic growth, tumor survival and chemoresistance in MCL cells. SOX11+/MSI2 high MCL primary leukemic samples showed higher percentage of ALDH+ cells compared to SOX11-/MSI2 low samples, which decreased after Ro 08-2750 treatment. Besides, MSI2 silencing delayed tumor growth in vivo in MCL xenograft mice models. Summary/Conclusion: Overall, our results suggest that MSI2 might play a key role in sustaining stemness, chemoresistance and tumor cell survival in MCL. MSI2 represents a potential novel target for therapeutic interventions in MCL.
A Personalized Approach to Prevention of Venous Thromboembolism
Authors: Anahita Dua, Monica Majumdar, Shipra Arya
Journal: JAMA Surgery (2022)

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Does nonalcoholic fatty liver disease predispose patients to carotid arteriosclerosis and ischemic stroke?
Authors: Qian Jin, Rui-Xu Yang, Jian-Gao Fan
Journal: Clinical and Molecular Hepatology (2022)

See the Original "Non-alcoholic fatty liver disease increases risk of carotid atherosclerosis and ischemic stroke: An updated meta-analysis with 135,602 individuals" on page 483.
P483: STAT3 DRIVES IMMUNE EVASION OF MLL-AF9-DRIVEN ACUTE MYELOID LEUKEMIA
Authors: B. Zdarsky, A. Witalisz-Siepracka, S. Boigenzahn, K. Fiedler, D. Stoiber
Journal: HemaSphere (2022)

Background: Acute myeloid leukemia (AML) is a heterogenous disease with poor prognosis. Although the treatment opportunities in AML expanded in recent years, relapse still remains a major issue and novel therapies aiming to eradicate minimal residual disease are needed. Natural killer (NK) cell immunotherapy is put forward as a potential strategy fulfilling these unmet clinical needs. Importantly, NK cell function of AML patients is largely diminished due to different mechanisms of tumor-mediated immune suppression and escape. Signal transducer and activator of transcription 3 (STAT3) is a member of the JAK-STAT signaling pathway driving transcriptional responses downstream of many cytokines. To escape the immune surveillance, tumor cells tend to downregulate NK cell responses and STAT3 was proposed to drive this process in solid cancers. Aims: We aim to investigate the function of STAT3 in AML evasion from NK cell surveillance. Methods: Using CRISPR/Cas9 we generated STAT3-deficient human AML cell lines carrying the MLL-AF9 oncogene. The cell lines were characterized via flow cytometry, Western blot and qPCR and used as target cells for a human NK cell line in cytotoxicity assays. Results: Using publicly available databases, we show that STAT3 expression negatively correlates with several NK cell-activating ligands in AML patients. Moreover, when studying a panel of human AML cell lines with a range of STAT3 expression levels, we observed a trend for the most efficient NK-cell mediated killing in cell lines expressing the lowest levels of STAT3. AML cells lacking STAT3 showed no major impairment in survival and proliferation under homeostatic conditions but were less resistant to different types of cellular stress. Interestingly, loss of STAT3 significantly enhanced killing by NK cells. The effect was also supported by elevated expression of NK-activating ligands in STAT3-deficient cells. We are currently testing if STAT3 inhibition recapitulates the observed effect. Summary/Conclusion: Our in vitro data indicate that targeting STAT3 in AML might be a strategy to enhance NK cell-mediated killing. We plan to extrapolate our findings into in vivo xenograft systems with adoptive transplants of primary human NK cells. The study will provide important insights into AML evasion from NK cell-mediated surveillance and potentially give a novel rationale for STAT3 inhibition in AML.
S279: INCREASED RISK OF INFECTIONS IN INDIVIDUALS WITH HEMOCHROMATOSIS C282Y HOMOZYGOSITY AND IN INDIVIDUALS WITH HIGH OR LOW PLASMA IRON OR TRANSFERRIN SATURATION: A PROSPECTIVE STUDY OF 138252 INDIVIDUALS
Authors: M. Mottelson, A. Glenthøj, B. Nordestgaard, C. Ellervik, S. Bojesen, J. Helby
Journal: HemaSphere (2022)

Background: Plasma iron and transferrin saturation are measures of iron available in the blood stream. Plasma ferritin indicate body iron stores. Levels of plasma iron, transferrin saturation and ferritin are increased in hemochromatosis C282Y homozygous individuals. Aims: We tested the hypothesis that high and low plasma iron and transferrin saturation are associated with increased risk of infections observationally and genetically through hemochromatosis C282Y homozygosity. Methods: We studied 138,252 general population individuals. Plasma iron and transferrin saturation were measured in 136,656 and 136,599 individuals, respectively. 132,542 individuals were genotyped for the C282Y hemochromatosis variant. Individuals were followed prospectively for up to 28 years for hospital admissions and emergency room visits due to infectious diseases using the National Patient Register which covers all danish hospitals. Results: During follow-up 31,199 individuals were hospitalized due to an infection. After multivariable adjustment including other risk factors for infections, individuals with the 5% lowest and 5% highest plasma iron levels had hazard ratios for any infection of 1.20 (95% CI:1.12-1.28;P<0.001) and 1.14 (95% CI:1.07-1.22;P<0.001) respectively, when compared to individuals with plasma iron levels between the 25th-75th percentile. Findings for transferrin saturation were similar. Hazard ratio for any infection in hemochromatosis C282Y homozygous individuals was 1.40 (95% CI:1.16-1.69; P<0.001) when compared to wildtype individuals. Risk of sepsis was especially high in C282Y homozygotes (hazard ratio 1.69;95% CI:1.05-2.73; P=0.03). Risk of any infection was increased even in C282Y homozygotes with normal levels of plasma iron, transferrin saturation or ferritin. Summary/Conclusion: High and low plasma iron and transferrin saturation were associated with increased risk of infections. Hemochromatosis C282Y homozygotes had increased risk of infection even when they had normal levels of plasma iron, transferrin saturation or ferritin. Current hemochromatosis treatment strategy centralized around ferritin normalization may not reduce risk of infection satisfactorily in patients with hereditary hemochromatosis genotype.
P1208: CHARACTERISTICS AND CLINICAL OUTCOMES OF PATIENTS WITH ALK-POSITIVE ANAPLASTIC LARGE CELL LYMPHOMA: REPORT FROM THE PROSPECTIVE INTERNATIONAL T-CELL LYMPHOMA PROJECT
Authors: C. Chiattone, M. Civallero, T. Fischer, E. Miranda, M. Manni, N. P. C. Zing, S. A. Pileri, S. Montoto, S. M. Horwitz, M. E. Cabrera, C. A. De Souza, A. Nagler, S. Luminari, A. J. M. Ferreri, K. R. Carson, A. Re, L. Rigacci, L. Nassi, M. Federico, G. Inghirami
Journal: HemaSphere (2022)

Background: Anaplastic large cell lymphoma kinase-positive (ALCL, ALK+) is a distinct lymphoid neoplasm whose malignant cells express CD30 (TNFR8), and carrying translocations of the anaplastic lymphoma kinase. Downstream ALK signaling cascades modulate both anti apoptotic signals and growth patterns fostering lymphoma proliferation and promoting an aggressive clinical behavior. T-cell Lymphoma Project (TCP) is the largest prospective multicenter cohort study conducted in newly diagnosed PTCL patients. Herein, we report the analysis of demographics, initial clinical characteristics, treatment patterns, and outcomes in ALCL, ALK+ patients enrolled into the TCP database. Aims: We report the analysis of demographics, initial clinical characteristics, treatment patterns, and outcomes in ALCL, ALK+ patients enrolled into the TCP database. Methods: Seventy-four institutions from 14 countries in North America, South America, Europe, and Asia collected data on patients diagnosed and treated at respective centers between September 2006 and February 2018. One hundred thirty-one patients (8.4% of the total cohort) were confirmed to have anaplastic large cell lymphoma - kinase positive (ALCL, ALK+), among a total of 1553 PTCL patients Results: Patients’ median age was 39 years (18-84). Sixty-five patients (66%) had advanced-stage disease, although the majority (45 patients, 54%) had a low-risk International Prognostic Index score (0-1). Of 81 patients treated with chemotherapy, 97% received anthracycline-containing regimens. The overall response rate was 81%, with 69 patients (70%) achieving complete remission. OS and PFS estimated in 3 years were 77% (95% CI 55-99%) and 68% (95% CI 46-90%), respectively, and in 5 years were very similar 77% of OS (95% CI 62-92%) and 64% of PFS (95% CI 34-94%). Multivariate analysis for PFS the results were advanced stage (HR 4.72 95%CI: 1.43-23.9, P=0.015), elevated LDH (HR 4.85 95%CI: 1.73-13.60, P=0.014) and ECOG-PS≥2 (HR 5.25 95%CI: 1.68-16.4, P=0.024). Whereas for OS resulted elevated LDH (HR 3.77 95%CI: 1.98-14.17, P=0.014) and ECOG-PS ≥2 (HR 4.59 95%CI: 1.46-14.39, P=0.004). Summary/Conclusion: Considering the low incidence and PTCL heterogeneity, diagnostic algorithms and therapeutic guidelines remain challenging. Indeed, although CHOP-like regimens of ALCL ALK+‘s treatment lead to favorable responses, ~30% need a second-line therapy (refractory or relapsed patients). Developing more specific/effective first/second-line protocols to achieve long-term response rates/eradication and preserve safety profiles remain highly desirable. We anticipate that only international-based studies will improve our collective knowledge and ameliorate outcomes.
Molecular profiling identifies targeted therapy opportunities in pediatric solid cancer
Authors: Alanna J. Church, Laura B. Corson, Pei-Chi Kao, Alma Imamovic-Tuco, Deirdre Reidy, Duong Doan, Wenjun Kang, Navin Pinto, Luke Maese, Theodore W. Laetsch, AeRang Kim, Susan I. Colace, Margaret E. Macy, Mark A. Applebaum, Rochelle Bagatell, Amit J. Sabnis, Daniel A. Weiser, Julia L. Glade-Bender, Alan C. Homans, John Hipps, Haley Harris, Danielle Manning, Alyaa Al-Ibraheemi, Yvonne Li, Hersh Gupta, Andrew D. Cherniack, Ying-Chun Lo, Gianna R. Strand, Lobin A. Lee, R. Seth Pinches, Lorena Lazo De La Vega, Maegan V. Harden, Niall J. Lennon, Seong Choi, Hannah Comeau, Marian H. Harris, Suzanne J. Forrest, Catherine M. Clinton, Brian D. Crompton, Junne Kamihara, Laura E. MacConaill, Samuel L. Volchenboum, Neal I. Lindeman, Eliezer Van Allen, Steven G. DuBois, Wendy B. London, Katherine A. Janeway
Journal: Nature Medicine (2022)
P837: ELTROMBOPAG (EPAG) INDUCES HEMATOLOGIC RESPONSES FOR PATIENTS WITH POST-ALLOGENIC HEMATOPOIETIC STEM CELL TRANSPLANT POOR GRAFT FUNCTION (POST-ALLO HSCT PGF): RESULTS OF THE ELTION STUDY IN SPAIN
Authors: C. Vallejo, I. García, F. Sanchez Guijo, M. Cuesta, C. Solano, A. Sampol, T. Torrado, M. Vendranas, M. Marigil
Journal: HemaSphere (2022)

Background: Persistent cytopenia due to poor graft function (PGF) is a life-threatening complication in patients undergoing allogeneic HSCT (allo-HSCT). Several therapeutic approaches have been tested in this subset of patients with poor clinical results. Aims: The objective of this multicenter open-label interventional prospective phase II Novartis study (ELTION, ClinicalTrials.gov id: NCT03718533), was to analyze efficacy and safety of EPAG in patients with post-allo-HSCT poor graft function. Methods: Adult patients diagnosed with PGF (defined as severe cytopenia after day +30 post-transplant, with two or more of the following: platelets <20000/µL -mandatory-, ANC <1000/µL, hemoglobin< 10 g/dL), and full donor chimerism, were eligible to enter the trial. Study treatment consisted of EPAG. at 150 mg/day administered up to 36 weeks; dose adjustments were contemplated as per protocol on an individual basis. The primary efficacy endpoint was the overall hematologic response (partial and complete), as determined by platelet, hemoglobin and neutrophil counts by 16 weeks after the initiation of EPAG. Results: Although the aim of the study was to include 33 patients, recruitment stopped prematurely due to the difficulties for hospital visits posed during COVID-19 pandemic, and eventually only 10 patients were included. The decision for this premature termination is not related to any safety concern related to the drug. Patient characteristics are shown in the Table 1 attached below. At EPAG. initiation, all 10 patients showed thrombocytopenia (<20000/µcL), 5 presented with anemia (Hgb <10 g/dL), and 4 had neutropenia (ANC <1000/µcL). Four patients discontinued EPAG before week 12 due to: disease progression/relapse (2 patients), protocol deviation (1 patient), and CMV infection (1 patient). In none of the cases, the event was related to study drug. At week 16, 4 patients (4/10, 40%) and at week 24, 5 patients, showed improvement in at least one of the 3 hematologic cell lines (partial response), respectively. Counts pre- and post-EPAG and global response in patients who stayed on treatment > 12 weeks are displayed below: Image:Summary/Conclusion: In our experience, EPAG worked well in subjects with PGF, an otherwise life-threatening condition for patients, and its use at 150 mg/day is safe and well tolerated in this setting. Our data suggest that eltrombopag might improve hematologic cell counts in patients with PGF, especially in those patients who remained on treatment at week 24, however further research is warranted to extend its applicability for larger cohorts
Comparison of Society Guidelines for the Management and Surveillance of Pancreatic Cysts
Authors: Hassan Aziz, Alexandra W. Acher, Somashekar G. Krishna, Jordan M. Cloyd, Timothy M. Pawlik
Journal: JAMA Surgery (2022)

The identification of incidental pancreas cystic lesions (PCLs) has increased in recent decades with the expanded use and improved sensitivity of cross-sectional imaging. Because the overall risk of malignancy associated with PCLs is low, yet the relative morbidity of pancreatic surgery is high, evidence-based guidelines are necessary for appropriate surveillance and management. Therefore, this article provides a review of existing guidelines regarding surveillance and management of PCLs and highlights recent advances in the diagnostic evaluation of cysts and the postresection management of mucinous lesions.There are 5 main guidelines related to the management of PCLs: the American Gastrointestinal Association (AGA) guidelines, the American College of Gastroenterology (ACG) guidelines, the American College of Radiology (ACR) recommendations, the European evidence-based guidelines, and the International Association of Pancreatology (IAP)/Fukuoka guidelines. These guidelines are based on retrospective studies that do not account or control for most tumor- and patient-specific factors. These guidelines also vary in scope, recommendations for surgical resection vs surveillance, as well as duration and type of follow-up.PCL guidelines should be viewed within the context of the data limitations on which they are based. PCL subtype-specific guidelines on surveillance and treatment are needed. In the future, the integration of cyst-specific genomic analysis, as well as evolutions in advanced diagnostic tools, such as cyst fluid next-generation sequencing and EUS-guided confocal laser endomicroscopy, may also better inform treatment guidelines. Owing to the current low-quality evidence on which many guidelines are based and the inherent morbidity of pancreas surgery, it is imperative that patients with PCLs are referred to institutions with advanced diagnostics and a multidisciplinary approach to patient surveillance and management.